D. Chemistry Core The BCSC chemistry team has a strong record of performing effective follow-up chemistry in order to increase the value of small-molecule hits uncovered in screens, and we offer strong "hit-to-probe" optimization chemistry support for the MLPCN. This team will perform cheminformatics, synthetic medicinal chemistry and limited pharmacology to optimize active compounds discovered in the HTS Core. The extensive medicinal chemistry and drug development experience of the team will ensure that all chemical probes are well characterized, reliable and capable of providing valid information on their activity against the target of interest. The probe compounds will be produced at our facility on multi-gram scale to ensure that they are usable by the research community for in vitro and/or in vivo studies. The chemistry team has decades of experience converting initial screening hits into pharmaceutically relevant leads by tuning properties such as affinity, specificity, and solubility. Since hit optimization is a collaborative effort, co-localization of the screening center with the chemistry team will increase the efficiency of probe production. The Compound Probe Development Plan (CPDP) will include input from the assay development and counter-screen development teams. Our team, which includes 19 professional staff chemists (16 Ph.D.'s) and outstanding infrastructure, will enable us to generate 100-300 analogs within each CPDP, although it is our hope that our knowledge and experience will allow us to optimize any compound with even fewer analogs.